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CHAPTER 104 Delirium and Dementia
Jeffrey P. Smith and Jennifer Seirafi
PERSPECTIVE
Emergency physicians are frequently presented with patients
exhibiting neurobehavioral abnormalities. These can be a harbin­
ger of a serious medical condition, and critical decisions must
be made expeditiously about diagnostic evaluation, therapeutic
intervention, and disposition. The first critical action is to recog­
nize the presence of the neurobehavioral abnormality. The second
is to distinguish delirium from dementia or some other neuropsy­
chiatric condition.
In the past, terms such as acute confusional state, sundowning,
and organic brain syndrome have been used to describe a host
of abnormal cognitive states that can be observed in the emer­
gency setting. These terms have loosely defined a group of
neurobehavioral disorders that are caused by a physiologic dis­
turbance. Organic brain syndrome is a nebulous term that the
Diagnostic and Statistical Manual of Mental Disorders (fourth
edition, text revision) eschews because the “organic” connotation
implies that so-called functional mental disorders are without a
biologic basis.1
Several key features best distinguish delirium from dementia:
the time course of disease evolution, the presence of autonomic
system involvement, the level of consciousness, and the presence
of an underlying disease processes. Delirium is characterized by a
fluctuating level of neurobehavioral disturbance typically pro­
gressing during minutes to hours to days. Delirium is a direct
consequence of an acute systemic or central nervous system (CNS)
stressor. Dementia, on the other hand, tends to follow a more
gradual course, with evolution during months to years. Although
patients with dementia exhibit confusion, disturbance in level of
consciousness usually is not a feature, and manifestations of auto­
nomic nervous system abnormalities are minimal or absent.
The evaluation of patients who present to the emergency
department (ED) with a disturbance of neurobehavioral state
is best conducted in accordance with the following basic
guidelines:
1. The first step is to determine whether this state represents
delirium or dementia. The clinical findings may be subtle,
and establishment of the diagnosis can be challenging,
especially because delirium may be superimposed on
dementia and dementia remains an independent risk
factor for delirium.2,3 Early symptoms and signs may go
unrecognized unless an adequate history is obtained from
the patient, family members, and caregivers. A careful
examination must include memory and cognitive assessment
with a mental status screening examination.
2. Supportive care must be provided. This care may range in
extent from aggressive airway and cardiovascular support to
1398
pharmacologic or physical restraint to simply placing the
patient in a quiet room with appropriate environmental
support.
3. A diligent search must be initiated for the underlying
precipitating stressors in patients presenting with delirium.
DELIRIUM
Definition and Background
Delirium is a syndrome that can be defined as an acute or subacute
state of cognitive dysfunction caused by an underlying physiologic
condition. Terms that have been used interchangeably with delir­
ium include acute organic brain syndrome, acute confusional
state, reversible cerebral dysfunction, metabolic encephalopathy,
toxic encephalopathy, and febrile delirium. The word delirium is
derived from the Latin delirare, which literally means “to go out
of the furrow” (in a more modern sense, “to derail”), but it is used
figuratively to mean “crazy” or “deranged.”
Several key features are necessary for a diagnosis of delirium
(Box 104-1). Patients with delirium have disturbances in con­
sciousness, memory, cognition, and perception. These distur­
bances tend to develop during a short time (hours to days). The
disturbance in consciousness may be manifested initially as an
inability to focus attention. The fluctuating course of symptoms
and inattention are the hallmarks of delirium. Deficiencies in cog­
nition may be manifested by disorientation and memory deficits.
Perceptual disturbances include hallucinations and delusions. The
delirious patient may be somnolent or agitated, and the thought
process may range from mildly disturbed to grossly disorganized.
The clinical presentation may be subdued or explosive. The
patient’s sleep-wake cycle may be altered or reversed; agitation
often is present during the night. Historically, delirium referred to
a hyperactive state marked by agitation and emotional lability
(e.g., delirium tremens). An important point, however, is that
delirium has several psychomotor subtypes: hyperactive (mania),
hypoactive (depressed), and mixed type.4
The exact incidence of delirium in the overall ED population is
unknown. However, the prevalence of delirium among elders who
present to the ED is approximately 10 to 20%.5 Geriatric patients
are at particularly high risk for the development of delirium.
Advanced age, dementia, and underlying medical illness are
strongly associated with delirium. Multiple medications, drugs,
and alcohol also are associated with delirium.6 Severe psychologi­
cal stress and sleep deprivation may facilitate the development
of delirium.
Chapter 104 / Delirium and Dementia 1399
BOX 104-1 Diagnostic Criteria for Delirium
Four Key Characteristics
• Clouding of consciousness with reduced ability to focus,
sustain, or shift attention
• A cognitive change (e.g., memory deficit, disorientation,
language disturbance) or perceptual disturbance that is not
better accounted for by a preexisting, established, or evolving
dementia
• Development of the disturbance during hours to days, with a
tendency to fluctuate in the course of the day
• Evidence from the history, physical examination, or laboratory
studies that the disturbance is caused by a general medical
condition, medication or other substance exposure, substance
withdrawal, or multiple etiologic disorders
Additional features may include psychomotor behavioral
disturbances such as hypoactivity, hyperactivity with increased
sympathetic activity, and emotional lability.
Modified from American Psychiatric Association: Diagnostic and Statistical Manual
of Mental Disorders, 4th ed, text rev. Washington, DC, American Psychiatric
Association, 2000.
Pathophysiology
At a cellular level, delirium is the result of widespread alteration
in cerebral metabolic activity, with secondary deregulation of neu­
rotransmitter synthesis and metabolism. Both the cerebral cortex
and the subcortical structures are affected, producing changes in
arousal, alertness, attention, information processing, and the
normal sleep-wake cycle.
Although the exact pathophysiologic process is not well under­
stood, multiple neurotransmitters have been implicated in causing
delirium. One theory is that delirium is associated with a derange­
ment of central cholinergic transmission. Serum anticholinergic
activity is increased, and low levels of acetylcholine are seen in
older patients with delirium.7 Increased serotonin levels have been
found in hepatic encephalopathy, serotonin syndrome, sepsis, and
psychedelic drug ingestion.8 Some of the disturbances that occur
in delirium are deficiencies of substrates for oxidative metabolism
(e.g., glucose, oxygen); disturbances of ionic passage through
excitable membranes; increase in cytokines; imbalance of normal
noradrenergic, serotoninergic, dopaminergic, and cholinergic
homeostasis; and, in some cases, synthesis of false neurotransmit­
ters.9 Drugs and exogenous toxins can produce delirium through
direct effects on the CNS. Although the limbic system appears to
be particularly vulnerable to the effects of these drugs, the cerebral
hemispheres and the brainstem also can be profoundly affected.
Tricyclic antidepressants can cause delirium by cholinergic
inhibition; sedative-hypnotics depress activity in the CNS,
especially in the limbic system, thalamus, and hypothalamus. Nar­
cotics affect CNS activity primarily by interacting with various
opioid receptor sites. Depending on the opioid receptor type
affected, the physiologic response may be analgesia, euphoria,
sedation, dysphoria, delusions, or hallucinations. Psychedelic
drugs probably act as agonists at serotonin receptor sites. Phency­
clidine (PCP) inhibits reuptake of dopamine, norepinephrine,
serotonin, and α-aminobutyric acid and also may act as a false
neurotransmitter.
Hyperthermia and hypothermia can cause delirium, probably
as a result of changes in the cerebral metabolic rate. In hypother­
mia, cerebral metabolism decreases 6 to 7% for each 1° C decrease
in temperature from 35 to 25° C. In hyperthermia, cellular damage
with uncoupling of oxidative phosphorylation begins to occur at
temperatures higher than 42° C. Patients suffering from heatstroke
may have cerebral edema, degenerative neuronal changes (espe­
cially involving Purkinje cells of the cerebellum), and petechiae in
Causes of Delirium: “I Watch Death”
Table 104-1 Mnemonic
CAUSE
FORM
Infectious
Sepsis, encephalitis, meningitis, syphilis, central
nervous system abscess
Withdrawal
Alcohol, barbiturates, sedative-hypnotics
Acute metabolic
Acidosis, electrolyte disturbance, hepatic or renal
failure, other metabolic disturbances (↑ or ↓ glucose,
magnesium, calcium)
Trauma
Head trauma, burns
CNS disease
Hemorrhage, stroke, vasculitis, seizures, tumor
Hypoxia
Acute hypoxia, chronic lung disease, hypotension
Deficiencies
Vitamin B12, hypovitaminosis, niacin, thiamine
Environmental
Hypothermia, hyperthermia, endocrinopathies
(diabetes, adrenal, thyroid)
Acute vascular
Hypertensive emergency, subarachnoid hemorrhage,
sagittal vein thrombosis
Toxins or drugs
Medications, street drugs, alcohol, pesticides,
industrial poisons (e.g., carbon monoxide, cyanide,
solvents)
Heavy metals
Lead, mercury
Modified from Wise MG: Delirium: Differential diagnosis for delirium: Critical items
(I WATCH DEATH). In: Yudofsky SC, Hales RE (eds): The American Psychiatric Press
Textbook of Neuropsychiatry, 2nd ed. Washington, DC, American Psychiatric
Publishing, 1992.
the walls of the third and fourth ventricles. Delirium occurring at
temperatures below 40° C is multifactorial in origin and not
caused solely by increased core temperature.
Delirium caused by metabolic abnormalities, such as hypona­
tremia, hypernatremia, hyperosmolarity, hypercapnia, and hyper­
glycemic disorders, is associated with a variety of metabolic
disturbances at the neuronal and astrocyte levels. Such distur­
bances may include impairments in energy supplies, changes in
resting membrane potentials, changes in cellular morphology, and
changes in the brain water volume.
Most patients with delirium have reduced cerebral metabolic
activity. This reduction in cerebral metabolism is reflected by a
decrease in the frequency of background electrical activity on
the electroencephalogram (EEG). Exceptions are hyperthermia,
sedative-hypnotic withdrawal, delirium tremens, and certain
drug-induced states, in which the cerebral metabolism is either
normal or increased.
Etiology
The causes of delirium are legion (Table 104-1). Within the geri­
atric population, medications are a common cause of delirium,
whereas drugs (including ethanol) are the most common cause of
delirium in the younger adult population. Acute cognitive dys­
function may be secondary to drug overdose, withdrawal syn­
dromes, and adverse or idiosyncratic reactions.
The list of commonly prescribed drugs causing delirium is
extensive and includes antibiotics (antifungal, antimalarial, and
antiviral agents; numerous antibacterial agents, including the qui­
nolones and macrolides), anticholinergic drugs (antihistamines,
antispasmodics, muscle relaxants, tricyclic antidepressants), anti­
convulsants, anti-inflammatory agents (corticosteroids, salicy­
lates, and other nonsteroidal anti-inflammatory drugs), various
cardiovascular medications (beta-blockers, antidysrhythmics,
antihypertensives, cardiac glycosides), sympathomimetics (phen­
ylpropanolamine), sedative-hypnotics, narcotics (transdermal
1400 PART III ◆ Medicine and Surgery / Section Seven • Neurology
fentanyl [Duragesic], morphine sulfate [Roxanol], hydro­
morphone HCl [Dilaudid], oxycodone HCl [OxyContin]),
mis­cellaneous drugs (aminophylline, cimetidine, lithium, chlor­
propamide), over-the-counter medications with anticholinergic
properties, and caffeine-containing products.6
Many “street drugs” with significant abuse potential, such as
hallucinogens, amphetamines, PCP, cocaine, and methylenedioxy­
methamphetamine (MDMA, ecstasy), can cause delirium, as can
intoxication with any of the alcohols (e.g., ethanol, methanol,
ethylene glycol).
Exposure to industrial chemicals (e.g., carbon disulfide, heavy
metals, insecticides, cyanide, carbon monoxide) can cause a wide
range of symptoms that include acute delirium. In addition,
ingestion of certain plants (e.g., nutmeg, foxglove, jimsonweed,
psilocybin-containing mushrooms) can cause delirium.
Delirium can be one of the protean manifestations of a meta­
bolic or nutritional abnormality. The most common metabolic
disorder causing acute cognitive changes is diabetes mellitus.
Hypoglycemia is the most common and readily reversible
cause of acute confusion in the diabetic patient. Other causes
of acute cognitive impairment in the diabetic patient are
hyperglycemia, hyperosmolarity, and acid-base abnormalities.
Severe metabolic abnormalities, including electrolyte distur­
bances, hypoxemia, hepatic insufficiency, renal insufficiency, and
dysfunction of various endocrine glands (hyperthyroidism,
hypothy­roidism, Cushing’s syndrome, hyperparathyroidism, and
other endocrine disorders), can cause delirium. Deficiency of
niacin, pyridoxine, folic acid, or vitamin B12 may be associated
with an acute confusional state.
Delirium can be a prominent feature of any systemic infection,
particularly in the very young, elders, and immunocompromised
patients. Infectious and host factors together determine the degree
of cognitive impairment. Extracranial infections that are associ­
ated with delirium include sepsis (particularly gram-negative
sepsis), subacute bacterial endocarditis, Legionnaires’ disease,
Rocky Mountain spotted fever, malaria, typhoid fever, toxic shock
syndrome, and several viral infections including influenza. Patients
with CNS infections, including meningitis, encephalitis, and intra­
cerebral abscess, may have acute cognitive dysfunction.
Another less common cause of delirium is CNS infarction in
the distribution of the nondominant middle cerebral artery and
the posterior cerebral artery. In patients who have a collagen vas­
cular disease with CNS vasculitis, neuropsychiatric manifesta­
tions, including acute delirium, may be prominent. Paraneoplastic
syndromes may include encephalopathy, with symptoms of confu­
sion, catatonia, and dementia.
Patients who are immunocompromised may have multiple and
unusual causes of acute delirium. Patients with immunosuppres­
sion secondary to malignant disease, drugs, or human immuno­
deficiency virus type 1 (HIV-1) infection may have acute brain
dysfunction secondary to infection, complications of drug therapy,
or the underlying disease itself.
Acute confusional states have been reported to be a more
common herald of the onset of physical illness in the elderly than
are fever, pain, and tachycardia.2,3,10 Factors that predispose elders
to delirium include the effects of aging on the brain, reduced
capacity for homeostatic regulation, impaired vision and hearing,
and age-related changes in the pharmacokinetics and pharmaco­
dynamics of drugs.11 The etiology of delirium in elders is usually
multifactorial.
Clinical Features
The clinical manifestations of delirium are as variable as the
causes. The clinical presentation can be so subtle as to go unrec­
ognized or may be dramatic enough to disrupt the entire ED. The
natural history of a patient’s delirium can progress from apathy
to marked agitation in the course of hours (see Box 104-1). Non­
specific prodromal symptoms such as anxiety, restlessness, and
insomnia typically emerge during hours to days.
Key aspects of cognitive impairment should become evident
during a careful history and examination. Disturbance in atten­
tion is central to the diagnosis of delirium. The patient is easily
distractible and has difficulty remaining focused on a particular
topic or interacting with a single person. Disorientation often
accompanies the deficit inattention but is not an invariable feature.
The patient usually is disoriented with respect to time and occa­
sionally to place; in extreme cases, disorientation to person also
may be noted. Delirium, however, may be present in a patient who
is completely oriented to person, place, and time. A mental status
examination that consists solely of questions that assess orienta­
tion will not detect delirium in these instances.
The patient with delirium always has some degree of memory
impairment, with the greatest impact on short-term memory.
Thought processes and speech may be disorganized. Disturbance
in the sleep-wake cycle often occurs early in the course of delirium.
Perceptual disturbances, including misperception of the environ­
ment, poorly formed delusions, and hallucinations, are common.
The delirious patient may experience visual, auditory, tactile, gus­
tatory, or olfactory hallucinations, in contrast to patients with
acute functional psychosis, who typically experience only auditory
hallucinations. In addition, the delirious patient has a reduced
capacity to modulate fine emotional expression and may demon­
strate extreme emotional lability.
The cognitively impaired patient may provide an unreliable
history. Valuable information often can be obtained from family,
friends, and out-of-hospital personnel. Specific inquiry should be
made about the patient’s current medical problems and previous
medical history, including diabetes, hypertension, kidney or liver
disease, and any neurologic or psychiatric problems. It is impor­
tant to determine whether the patient is immunosuppressed or
has risk factors for immunosuppression. A detailed medication
history, including the use of prescribed and over-the-counter
medications, dietary supplements, and alcohol or other sub­
stances, is essential. Out-of-hospital personnel should be able to
provide information about the home environment, medication
bottles belonging to the patient or found near the patient, and the
possibility of trauma.
The physical examination should begin with a careful assess­
ment of vital signs including pulse oximetry and a pain assess­
ment. The delirious patient often exhibits abnormalities on such
evaluation, including elevated or decreased pulse, blood pressure,
respiratory rate, and temperature. The examination includes
assessment of the head for signs of trauma and the pupils for
symmetry of light reflex; funduscopic examination for hemor­
rhage or papilledema; examination of the ears for hemotympa­
num; evaluation of the neck for nuchal rigidity, bruits, and thyroid
enlargement; assessment of the heart and lungs; evaluation of the
abdomen for organomegaly and ascites; and examination of the
extremities for cyanosis. The skin should be carefully examined
for rashes, petechiae, ecchymosis, splinter hemorrhages, and
needle tracks. The neurologic examination includes assessment of
the cranial nerves, motor strength, sensation, and presence of
abnormal movements (e.g., tremor, asterixis, myoclonus). The
reflexes are assessed for symmetry and presence of hyperreflexia
or hyporeflexia. Findings that typically suggest either a metabolic
or a structural neurologic problem are not necessarily specific for
that category of disorder. For example, asterixis is a hallmark of
metabolic encephalopathy but can be seen in focal brain disease.
Likewise, focal neurologic signs that typically are associated with
structural CNS lesions also can be present in various metabolic
abnormalities, such as hypoglycemia, hyperglycemia, hepatic
encephalopathy, uremia, and hypercalcemia.
Chapter 104 / Delirium and Dementia 1401
The physical examination is not often helpful in determining
the specific drug or class of drugs causing acute cognitive impair­
ment. The one exception to this rule is toxidromes, which are
constellations of signs and symptoms characteristic of intoxica­
tion with certain drugs or classes of drugs (see Chapter 147).
A brief mental status examination should be performed in all
patients thought to have acute brain dysfunction. Although the
concept is rather obvious, few physicians proceed beyond ques­
tions about the patient’s orientation to person, place, and time
when assessing mental status. Failure to diagnose subtle forms of
delirium when they are present is directly related to omission of
mental status testing.12
Several standardized tools for assessment of mental status have
been successfully applied in the ED.12-14 Mental status testing
includes assessment of orientation, memory, attention, and con­
centration; several tests also incorporate assessments of construc­
tional tasks, spatial discrimination, arithmetic ability, and writing.
Cognitive functioning can be rapidly assessed in approximately 7
to 10 minutes. Memory assessment requires testing of the patient’s
ability to repeat short series of words or numbers (immediate
recall), to learn new information (short-term memory), and to
retrieve previously stored information (long-term memory). Con­
structional apraxia is assessed by having the patient perform tasks
such as drawing interlocking geometric figures or clock faces and
connecting dots. Dysnomia (inability to name objects correctly)
and dysgraphia (impaired writing ability) are two of the most
sensitive indicators of delirium. Almost all acutely confused
patients exhibit writing impairments, including spatial disorgani­
zation, misspelling, and tremor.13,15
No single bedside cognitive test that can be administered quickly
is ideal. The Mini-Mental State Examination (MMSE) developed
by Folstein and colleagues has been validated more than any other
test and most frequently is recommended as a rapid screening
tool.10,13,15,16 For hospitalized patients, this test has a sensitivity of
87% and a specificity of 82% for detection of organic brain syn­
drome. Some investigators report slightly better results when the
test is modified and age is added as a variable in the analysis.16 The
MMSE does not measure executive function and is insensitive for
detection of early signs of mild cognitive impairment (without
dementia) or early dementia.17
The MMSE consists of a short series of questions that test ori­
entation, registration (memory), attention, calculation, recall, and
language (Fig. 104-1). The time for the test to be administered can
be reduced to 5 minutes by elimination of the writing and drawing
components with only a modest reduction in sensitivity. The reg­
istration section tests both immediate and short-term memory;
the recall section also assesses short-term memory. The ability to
recall two of three objects has 81% sensitivity and 74% specificity
for exclusion of organic brain syndrome. Asking the patient to
subtract “serial sevens” backward from 100 assesses attention, con­
centration, and arithmetic ability. This test is specific but not
sensitive for absence of an organic brain syndrome; up to 40% of
nondelirious, nondemented people fail to perform the tasks of this
test correctly, reflecting limitations due to language ability and
education. A total score of 23 or less is considered markedly
abnormal and indicates an organic brain syndrome. As a general
rule, patients with mild cognitive impairment have a score of 18
to 26 of 30, those with moderate impairment have a score of
10 to 18, and those with severe impairment have a score of
less than 10.
The Quick Confusion Scale represents another attempt to
quantify the attention aspects of mental status (see Chapter 17,
Fig. 17-2). It has significant correlation with the MMSE, can be
administered more quickly, and does not require constructional
tasks.18 Another useful diagnostic tool is the Confusion Assess­
ment Method; it has a sensitivity of 93 to 100% and specificity
of 90 to 95%.19 This simple tool has four key features used for
Maximum
Orientation
Score
5
What is the (year)(season)(date)(day)(month)?
5
Where are we (city)(state)(country)(hospital)(floor)?
Registration
3
Name three objects: one second to say each. Ask
the patient for all three after you have said them.
Give one point for each correct answer. Repeat them
until all three are learned. Count trials and record
number.
Attention and calculation
5
Serial sevens backwards from 100 (stop after five
answers). Alternatively, spell WORLD backward.
Recall
3
Ask for the three objects repeated above. Give one
point for each correct answer.
Language and praxis
2
Show a pencil and watch, and ask subject to name
them.
1
Ask the patient to repeat the following: “no ifs, ands,
or buts.”
3
Three-stage command: “Take this paper in your
right hand, fold it in half, and put it on the floor.”
1
Read and obey the following: “Close your eyes.”
(Written on a piece of paper.)
1
Write a sentence. (Must contain a noun and a verb
and be sensible. Ignore grammar and punctuation.)
1
Copy this design (interlocking pentagons). Must
contain all angles and two must intersect.
Figure 104-1. Mini-Mental State Examination. (Adapted from Folstein
MF, Folstein SE, McHugh PR: “Mini-mental state”: A practical method
for grading the cognitive state of patients for the clinician. J Psychiatr
Res 12:189, 1975.)
screening of delirium: acute onset and fluctuating course, inatten­
tion, disorganized thinking, and altered level of consciousness. For
a definitive diagnosis of delirium, the first two features and one of
the last two must be present. It has proved to be a valuable tool
because of its ease and interobserver reliability. In addition, it has
been shown to be more sensitive than clinical impression alone.18,20
The Six-Item Screener is another brief test of cognition that was
found to be 94% sensitive and 86% specific in identifying distur­
bance of cognition in older patients.15
All bedside tests of cognition have limitations and can miss mild
degrees of impairment. The patient’s level of education and
general intelligence can substantially affect the outcome. Further­
more, a single bedside test reflects a patient’s cognitive functioning
at only one point in time. For a diagnosis of delirium (or demen­
tia) to be established, an essential criterion is a documented
decline from the patient’s baseline level of cognitive functioning,
1402 PART III ◆ Medicine and Surgery / Section Seven • Neurology
and the sensitivity of these tests increases when they are repeated
over time.
Diagnostic Evaluation
and Ancillary Studies
Some reversible causes of delirium can be diagnosed by a number
of basic, readily available tests. The following laboratory tests can
be helpful in evaluation of the delirious patient: a complete blood
count (CBC; hemoglobin, leukocyte count with differential, plate­
let count, and mean corpuscle volume), serum electrolyte values,
glucose concentration, calcium concentration, and urinalysis. The
CBC may suggest unusual but potentially treatable abnormalities,
such as thrombotic thrombocytopenic purpura, megaloblastic
anemia, hyperviscosity from myelogenous leukemia, and unsus­
pected infection. The anion gap should be determined in all
patients with altered mental status. An elevated anion gap
(>15 mEq/L) may indicate the presence of unmeasured anions,
such as sulfate in renal failure; keto acids in diabetic or alcoholic
ketoacidosis; lactate in postictal states or associated with hypoten­
sion; and exogenous toxins, such as ethylene glycol, methanol, and
salicylates. A pulse oximetry measurement should be obtained in
all patients to screen for hypoxemia, and an arterial blood gas
analysis is warranted in those patients at risk for respiratory failure
with carbon dioxide retention. Suspected occult infection war­
rants urinalysis and chest radiography. In elders, an electrocardio­
gram should be obtained to exclude a silent acute coronary
syndrome. Ammonia level should be considered in patients with
cirrhosis, ascites, or asterixis. Despite these diagnostic evaluations,
no cause is found for delirium in up to 16% of patients.6
Toxicology screens are overused as diagnostic tests and have
limited usefulness in the evaluation of most patients with delir­
ium. Additional laboratory studies outside the scope of the ED
evaluation that may be appropriate when the cause of delirium
remains unknown include thyroid function studies, vitamin B12
and folic acid assays, rapid plasma reagin test, measurement of
serum antinuclear antibodies, urinary porphobilinogen assay, and
screens for heavy metals.
Patients with a history of trauma (especially those taking
anticoagulant medications), previous neurosurgical procedures,
immunodeficiency, or focal neurologic signs require a head com­
puted tomography (CT) scan to detect structural lesions causing
delirium. Early infarctions, small brainstem lesions, meningitis or
encephalitis, closed head injuries, sagittal vein thrombosis, and
small isodense subdural hematomas may be missed on a CT scan.
In addition, approximately 2 to 8% of acute subarachnoid hemor­
rhages are not detected by head CT scan and require lumbar
puncture for diagnosis. The role of magnetic resonance imaging
(MRI) in the evaluation of the delirious patient has not been
clearly established. MRI is superior to CT for detection of small
intercerebral and brainstem lesions, small brain contusions,
certain encephalitides, and abnormalities of white matter (e.g.,
leukoencephalopathy). MRI perfusion scans are more sensitive in
detecting an acute vascular event.
Cerebrospinal fluid (CSF) analysis is an essential part of the
evaluation in selected patients with delirium. In patients with fever
and cognitive dysfunction, even without meningismus, a lumbar
puncture should be performed to rule out meningitis. This test is
particularly important in the very young, elders, and immuno­
compromised patients, who are less likely to show classic signs of
meningitis. Patients with focal neurologic deficits, immunocom­
promised states, or evidence of increased intracranial pressure
should undergo head CT before lumbar puncture, and they should
receive antibiotics before the CT scan.
Although it is rarely practical in the ED setting, the EEG can
be a valuable diagnostic tool in determining the presence of
delirium. Bilateral diffuse symmetrical electroencephalographic
Table 104-2 Comparison of Delirium and Acute Psychosis
CHARACTERISTIC
DELIRIUM
ACUTE PSYCHOSIS
Onset
Acute
Acute
Vital signs
Typically abnormal
(fever, tachycardia)
Normal
Prior psychiatric
history
Uncommon
Common
Course
Rapid, fluctuating
Stable
Psychomotor activity
Variable
Variable
Involuntary activity
Possible asterixis,
tremor
Absent
Usually impaired
Globally impaired
Globally impaired
Visual, visual and
auditory
Transient, poorly
organized
Pressured, slow,
possibly incoherent
Occasionally impaired
May be disorganized
Impaired
Primarily auditory
Typically resolves
Responds to therapy,
recurrence common
Cognition function
Orientation
Attention
Concentration
Hallucinations
Delusions
Speech
Course
Systematized
Usually coherent
abnormalities are a relatively consistent feature of delirium. In
most cases, the changes consist of a nonspecific generalized
slowing from the baseline activity and can be useful in distinguish­
ing delirium from other neurobehavioral abnormalities.
Differential Diagnosis
Considerations in the differential diagnosis for apparent delirium
include functional psychiatric disorders and dementia. Depres­
sion, mania, paranoia, and schizophrenia all may resemble delir­
ium. Several clinical features are helpful in distinguishing between
organic and functional syndromes (Table 104-2).
Dementia, like delirium, is characterized by global cognitive
impairment. Unlike delirium, dementia tends to be an insidious
process that develops during months to years with little fluctua­
tion during hours or days. Typically, the patient’s vital signs are
normal. Dementia occurs primarily in the elderly. A point worthy
of emphasis is that patients with dementia are five times more
likely to develop delirium.2,3,5,6
Management
Delirium constitutes a medical emergency. The outcome depends
on the cause of the delirium, the patient’s overall health status, and
the timeliness of treatment. The presence of hyperactive or hypo­
active delirium has some prognostic significance.2 The hypoactive
form of delirium tends to be more common in elders and carries
a worse overall prognosis, perhaps because it often goes unrecog­
nized. Acute recognition and management of delirium in elders
are essential because delirium in this population is associated with
increased risk of long-term institutionalization, development of
dementia, and increased overall mortality.21
Patients who present with acute delirium should be screened
quickly for readily reversible causes, such as hypoglycemia,
hypoxia, and narcotic overdose. Acute intoxication from a number
of drugs or chemical agents, including tricyclic antidepressants,
ethylene glycol, cholinesterase inhibitors, anticholinergic agents,
carbon monoxide, and cyanide, requires prompt attention.
Although supportive measures are the mainstay of treatment in
Chapter 104 / Delirium and Dementia 1403
most poisonings and intoxications, most of these toxins have spe­
cific antidotes.
Other conditions requiring immediate medical intervention
include infections. Patients with signs of acute meningitis or
sepsis should receive antibiotics within 30 minutes of arrival to
the ED along with appropriate fluid resuscitation. Other emergent
conditions that may be manifested with delirium and necessitate
immediate intervention include severe hypothermia, hyperther­
mia, and CNS vascular conditions, including hypertensive enceph­
alopathy, acute epidural or subdural hematoma, subarachnoid
hemorrhage, and stroke. Patients with Wernicke’s encephalopathy
require immediate treatment with 100 mg of intravenous thia­
mine, with titration of additional doses until the ophthalmoplegia
resolves. Resistance to thiamine may result from hypomagnesemia
because magnesium is a cofactor for thiamine transketolase.
Glucose administration in patients with severe thiamine defi­
ciency may precipitate Wernicke’s encephalopathy. The specific
treatment of delirium tremens (and other alcohol withdrawal syn­
dromes) involves the substitution of a long-acting drug that is
cross-tolerant with the alcohol. Benzodiazepines are the agents of
choice to induce sedation. Delirium secondary to dehydration,
hyponatremia, hypernatremia, hypercalcemia, and hepatic or
renal disease gradually resolves during hours to days with appro­
priate treatment.
Supportive care for all patients with delirium includes provision
of an appropriate environment with adequate lighting, minimiza­
tion of sensory overload, placement of the patient in an area that
can be easily observed by staff, and use of stretcher side rails to
prevent falls. Use of “sitters” may be necessary because patients
may require constant supervision. It is important to protect the
patient from self-harm or from injuring other patients or staff. In
cases of hyperactive delirium, the patient may need to be initially
restrained physically until pharmacologic control takes effect.
Restraints should be viewed only as a temporizing action because
they can increase agitation and the risk of injury to the patient.
Physical restraints in agitated patients have been associated with
significant injuries and even death by asphyxiation and are not a
substitute for pharmacologic control.22,23
Pharmacologic restraint has become the cornerstone of
behavioral management. Classes of drugs that have been used for
management of delirium include the antipsychotics and benzodi­
azepines. The ideal sedating drug should have the following char­
acteristics: low toxicity with minimal anticholinergic effects, ease
of administration, short half-life, minimal effects on the cardio­
vascular and respiratory systems, and no effect on the seizure
threshold. Antipsychotic medications used to treat delirium
include the butyrophenones and the newer atypical antipsychotic
agents.24-29 Although no one drug is ideal, the butyrophenones,
specifically haloperidol (Haldol), are considered the agents of
choice for control of agitation in acute delirium on the basis of
extensive clinical experience.23,24 Increasing evidence indicates that
compared with haloperidol, the newer atypical antipsychotic
agents (risperidone, olanzapine, ziprasidone, aripiprazole) may
have equal or better efficacy and fewer side effects (especially
akathisia and dystonia) for management of acute agitation.25-29 In
addition, the atypical antipsychotic agents received a black box
warning from the U.S. Food and Drug Administration (FDA) in
2005 for use in elderly demented patients with agitation because
of the increased mortality noted in this special population
of patients (although this is associated with long-term use).30
Phenothiazines and droperidol, a butyrophenone pharmacologi­
cally similar to haloperidol, can cause orthostatic hypotension,
lower the seizure threshold, and have anticholinergic effects,
making them unacceptable for the treatment of delirium. The
use of droperidol for management of agitation has been signifi­
cantly curtailed since the FDA gave this drug a black box warning
because of the association of droperidol use with QT prolongation
and torsades de pointes; however, many clinicians think that
the warning is unjustified.31,32 The opioids morphine and meperi­
dine (Demerol) are capable of inducing dysphoria and can
exacerbate respiratory depression and hepatic encephalopathy
and should not be used for behavior control in the agitated
delirious patient.
Benzodiazepines are the drugs of choice for management of
delirium caused by withdrawal from alcohol or sedative-hypnotics,
for which a long duration of action is desirable. Lorazepam, a
shorter-acting benzodiazepam that undergoes glucuronide conju­
gation with rapid renal clearance, is the preferred agent for treat­
ment of withdrawal symptoms. In general, they are not indicated
in the management of symptoms of delirium caused by other
conditions.33 Although limited data exist, the benzodiazepines
may be helpful with ingestion of stimulants such as hallucinogens,
cocaine, and PCP. The benzodiazepine diazepam (Valium) should
be avoided as an agent for treatment of agitated behavior in most
delirious patients because of its long half-life, respiratory depres­
sant effect, and risk of drug accumulation with repeated dosing.
Benzodiazepines can worsen confusion, and use of this class
of drugs is an independent risk factor for delirium, especially in
the elderly.34,35
As the primary drug for control of hyperactive delirium, halo­
peridol is a potent dopamine-blocking medication with virtually
no anticholinergic and minimal hypotensive effects. The main
effect of the drug acutely is tranquilization. The drug can be easily
titrated with intravenous administration. The incidence of extra­
pyramidal side effects in patients receiving intravenous haloperi­
dol for management of delirium with agitation is relatively low.
Studies of the acute administration of haloperidol report an 8 to
30% incidence of extrapyramidal side effects, with akathisias being
most common and acute dystonia occurring in less than 10% of
patients.36 Haloperidol can prolong the QTc interval, but this
effect is clinically insignificant in most patients and does not
require a pretreatment electrocardiogram. Caution is warranted
with use of this agent in patients taking medications that prolong
the QTc (e.g., class IA and class III antiarrhythmics, certain anti­
biotics, inhibitors of the cytochrome P450 system) and in patients
with acute coronary ischemia, uncompensated congestive heart
failure, or hepatic dysfunction.37 Dosing should vary with the
patient’s level of agitation, age, weight, and response to treatment.
In most patients, 5 to 10 mg intravenously or intramuscularly is
well tolerated as an initial dose, and levels can be titrated as
needed. Higher doses may be required for younger patients. Daily
doses in excess of 200 mg for 15 consecutive days have been given
safely to agitated patients in the critical care setting.35 For elders,
a lower initial dose of 0.50 to 1.0 mg is recommended.38
Several well-controlled studies have shown that the combina­
tion of haloperidol and lorazepam (given by either the intramus­
cular or intravenous route) can achieve more rapid control of
agitated behavior than is possible with haloperidol alone and can
reduce the already low incidence of extrapyramidal neuromuscu­
lar symptoms.39,40
The atypical antipsychotics can be used acutely for manage­
ment of agitation. These drugs have multiple mechanisms of
action including antagonism of alpha2-adrenergic, serotonin,
muscarinic, dopamine, and histamine receptors. These drugs
block the reuptake of dopamine and serotonin, and the newer
drugs also have dopamine agonist effects (aripiprazole).41-44 Com­
pared with haloperidol, several of these atypical agents (ziprasi­
done, risperidone, clozapine, and olanzapine) have been shown in
nonrandomized case series to control agitation as effectively with
less sedation and fewer extrapyramidal side effects.41-44 Because of
the limited dopamine antagonism effect, atypical antipsychotics
are the preferred agent for patients with parkinsonism and agita­
tion. Atypical antipsychotic agents for management of acute agita­
tion have been slow to be adopted in clinical practice because of
1404 PART III ◆ Medicine and Surgery / Section Seven • Neurology
the limited studies (no randomized controlled studies in the ED
setting) and the significant clinical experience with haloperidol
and lorazepam.
It is not possible to obtain informed consent for proposed diag­
nostic and therapeutic interventions from a patient suffering from
delirium. In such cases, implied consent exists when a true emer­
gency is present or clinically suspected because common law rec­
ognizes that a reasonable person would want to receive treatment
in a true emergency even if impaired awareness at the time of
treatment precludes giving of informed consent. Thus it is appro­
priate to render treatment without informed consent to a patient
who lacks decision-making capacity in a life-threatening emer­
gency situation unless an advanced directive is available indicating
the patient’s desire to forgo treatment.45
Disposition
Patients with delirium secondary to acute drug intoxication may
be discharged from the ED, provided the process readily reverses
itself during a short period of observation and the drug has no
potentially serious delayed toxicity. For most patients delirious
from metabolic, infectious, or CNS processes, admission to the
hospital is necessary for further diagnostic evaluation and treat­
ment. The only readily reversible metabolic problem associated
with delirium that can be completely managed in the ED is
hypoglycemia.
For most patients without significant underlying medical illness
who have delirium, the outcome is full recovery. After an episode
of acute delirium, younger patients may experience mild cognitive
dysfunction that lasts weeks to months. Geriatric patients, on the
other hand, often experience persistent decline in their baseline
level of functioning, with loss of at least one activity of daily living
after acute delirium.46 Delirium in elders hospitalized without
baseline dementia is associated with higher 1-year mortality rates,
higher rates of institutionalization, and a greater risk for develop­
ment of dementia.21,47 For elders, an episode of delirium, especially
for those with baseline cognitive impairment, can have significant
long-term consequences despite good supportive multidisci­
plinary care.48
DEMENTIA
Definition and Background
Dementia is not a single disease entity but rather a highly variable
clinical syndrome characterized by a gradually progressive dete­
rioration of cognitive function. As with delirium, potential causes
are varied and numerous, and the prognosis depends on the
underlying cause. A particular dementia can be classified as either
potentially reversible or irreversible. Most patients with dementia
have an irreversible disease process; during the past several years,
the prevalence of reversible dementia has fallen to between 3 and
10%, with depression, hydrocephalus, subdural hematomas, drugs,
and alcohol dependence syndrome accounting for a majority of
cases.49,50 The goals of ED evaluation for suspected dementia are
(1) to recognize the signs and symptoms of potentially reversible
forms of dementia, (2) to identify the manifestations of acute
illness in the demented patient promptly, and (3) to assess the
findings for congruency with the normal progression of the irre­
versible dementias.
In 1907, Alzheimer described the clinical history and postmor­
tem findings for a 50-year-old woman with progressive demen­
tia.51 For decades, Alzheimer’s disease was considered to be an
uncommon dementia of younger patients known as presenile
dementia. The more common dementia of elders was believed to
be caused by atherosclerotic cerebrovascular disease and was
referred to as senile dementia. During the past several decades,
BOX 104-2 Diagnostic Criteria for Dementia
A. The development of multiple cognitive deficits manifested by
both of the following:
1. Memory impairment (impaired ability to learn new
information or to recall previously learned information)
2. One (or more) of the following cognitive disturbances:
a. Aphasia (language disturbance)
b. Apraxia (impaired ability to carry out motor activities
despite intact motor function)
c. Agnosia (failure to recognize or identify objects)
d. Disturbance in executive functioning (e.g., planning,
organization, sequencing, abstracting)
B. The cognitive deficits cause significant impairment in social
or occupational functioning and represent a significant
decline from a previous level of functioning.
C. The deficits do not occur exclusively during the course of
a delirium.
Adapted from American Psychiatric Association: Diagnostic and Statistical Manual
of Mental Disorders, 4th ed, text rev. Washington, DC, American Psychiatric
Association, 2000.
research has shown that the neuropathologic changes in the two
entities are identical. Today, these two categories of primary
degenerative dementias are collectively referred to as Alzheimer’s
disease. Alzheimer’s disease accounts for 60% of all dementias;
vascular dementia (with or without Alzheimer’s disease) accounts
for 20%, and the remaining 20% of cases are attributable to more
than 50 known causes.52
Worldwide, approximately 24.3 million persons suffer from
dementia, and 4.6 million new cases are diagnosed yearly.52 The
prevalence is approximately 1% at the age of 60 years but doubles
every 5 years until it reaches 30 to 50% by the age of 85 years. The
National Institutes of Health calculates that by 2030 there will be
approximately 10 million people with Alzheimer’s disease in the
United States.53,54
The American Psychiatric Association has defined criteria nec­
essary for the diagnosis of dementia (Box 104-2). There must
be impairment in both memory and cognitive function. Several
clinical features deserve emphasis. Intellectual impairment must
involve both short-term and long-term memory. The cognitive
impairment commonly involves abstract thinking, judgment, and
other higher cortical functions. The cognitive disturbance must
significantly interfere with interpersonal relationships, work, and
social activities of the affected person. Although mild decline in
intellectual functioning can be part of the normal aging process,
gross intellectual impairment and confusion should not be con­
sidered part of normal aging. Mild cognitive impairment is dis­
tinct from early dementia in that impairment involves mild
memory deficits; some believe that mild cognitive impairment is
a precursor to the development of Alzheimer’s disease.55
Dementia can be classified according to the degree of cognitive
impairment. Mild dementia implies some impairment of work
and social activities; however, the capacity for independent ade­
quate personal hygiene and independent living remains intact.
With moderate dementia, independent living is hazardous, and
some degree of supervision is necessary. With severe dementia,
continual supervision and often custodial care are needed.
Demented patients often have longer hospitalizations for the
same acute medical illness compared with those without demen­
tia, and the life expectancy of demented patients is 6 to 8 years less
than that of nondemented age-matched control subjects.56
Etiology
Dementia may be caused by more than 50 different disease states
(Box 104-3). Dementia may be broadly classified as either primary
Chapter 104 / Delirium and Dementia 1405
BOX 104-3 Classification of Dementias
Primary Cortical Dementias
Alzheimer’s disease
Pick’s disease
Primary Subcortical Dementias
Huntington’s chorea
Parkinson’s disease
Progressive supranuclear palsy
Secondary Dementias
Cerebrovascular disease (multi-infarct dementia)
Drug or toxin induced
Metabolic or electrolyte disturbance
Endocrinopathies
Infectious (intracranial) chronic meningitis, encephalitis, abscess,
HIV-1 infection, slow virus infection, neurosyphilis
Nutritional
Intracerebral disorders
Head trauma
Mass effect (tumor, hematoma, abscess)
Hydrocephalus
Psychiatric (pseudodementia)
Other (e.g., collagen vascular disease, paraneoplastic syndrome)
HIV-1, human immunodeficiency virus type 1.
degenerative dementia or secondary dementia; the secondary
dementia category includes the potentially reversible dementias.
Primary degenerative dementias include Alzheimer’s disease,
dementia with Lewy bodies, subcortical dementias involving the
basal ganglia and thalamus (e.g., progressive supranuclear palsy,
Huntington’s chorea, Parkinson’s disease), and dementia of the
frontal lobe type, which includes Pick’s disease. Dementia with
Lewy bodies, clinically manifested by persistent, well-formed
visual hallucinations and prominent extrapyramidal movements,
has been found to be the third most common type of dementia.
With advanced aging, dementia may have mixed causes, with
Alzheimer’s disease and vascular dementia frequently coexisting.
A smaller percentage of dementias are attributable to causes such
as anoxic encephalopathy, hepatolenticular degeneration, tumors,
and slow virus infections.
Adverse drug reactions and metabolic abnormalities in patients
can cause either an acute delirium or a gradual progressive demen­
tia. Drug-induced dementia occurs primarily in elders and can be
caused by various psychotropic drugs, antihypertensive medica­
tions, anticonvulsants, anticholinergics, and miscellaneous medi­
cations such as l-dopa. Dementia also may be caused by heavy
metals and other exogenous agents, such as carbon monoxide,
carbon disulfide, and trichloroethylene.
Endocrinopathies that can cause secondary dementia include
hypothyroidism, hyperthyroidism, parathyroid disease, Addison’s
disease, Cushing’s disease, and panhypopituitarism. Nutritional
deficiencies that cause dementia include thiamine deficiency
(Wernicke’s syndrome), niacin deficiency (pellagra), vitamin B12
deficiency, and folate deficiency. Dementia can be caused by intra­
cranial space-occupying lesions and hydrocephalus. Repetitive
intracranial trauma resulting from contact sports can produce a
chronic organic brain syndrome without evidence of hematoma
or significant contusion (dementia pugilistica).57,58 Intracranial
processes that may eventually lead to a chronic organic brain
syndrome include infections with slow viruses, HIV-1 infection,
chronic meningitis (tubercular or fungal), brain abscess, and neu­
rosyphilis. In addition to primary HIV-1 CNS infection, toxoplas­
mosis, cryptococcal meningitis, malignant disease, and infections
due to herpesvirus, cytomegalovirus, varicella-zoster virus, and
papovavirus (progressive multifocal leukoencephalopathy) can
cause progressive cognitive impairment in this compromised
group of patients and must be excluded.59
Depression in elders may closely mimic dementia. Diagnosis of
pseudodementia or depression masquerading as dementia can be
difficult and may require therapeutic interventions to confirm the
clinical diagnosis of depression. Confounding the issue, depres­
sion often coexists with dementia; one study found that 40% of
patients with dementia were depressed.60 Depression, anxiety, and
apathy are common in the prodrome and course of Alzheimer’s
disease.60,61
Pathophysiology
Alzheimer’s disease is the best-understood dementia and involves
several characteristic anatomic, pathologic, and neurochemical
changes. The predominant change is cortical atrophy most promi­
nent in the temporal and hippocampal regions caused by progres­
sive synaptic and neuronal loss in the cerebral gray matter. This
atrophy generally is followed by loss of white matter (subcortical
atrophy). Cell loss does occur with the normal aging process but
not to the extent seen in dementia. Not all patients with dementia
have gross cerebral atrophy. There is no ischemic component to
Alzheimer’s disease.
Histologic features characteristic of Alzheimer’s disease include
extracellular deposition of β-amyloid protein and intracellular
neurofibrillary tangles contributing to neuron loss. The abnormal
processing of β-amyloid protein probably is central to the patho­
genesis of Alzheimer’s disease. The neurofibrillary tangles are
intraneuronal paired helical filaments composed of the abnor­
mally phosphorylated protein tau, the structural protein involved
in the regeneration of neurites. In demented patients, these tangles
occur in great numbers throughout the cerebral cortex; only
limited numbers can be seen in nondemented elders (primarily
in the hippocampus region) and in a variety of other diseases.
The density of neocortical tangles correlates with the severity of
dementia.56 Mounting evidence suggests that Aβ protein accumu­
lation triggers activation of cysteine aspartyl proteases (caspases)
with cleaving of the tau protein, leading to neurofibrillary tangles
and apoptosis. Senile plaques are extracellular lesions composed
of degenerating neuronal processes and abnormal β-amyloid
protein. These plaques are extensively spread throughout the cere­
bral cortex and do not correlate with the severity of dementia.62
Other consistent neurohistopathologic changes in Alzheimer’s
disease include granulovascular degeneration, Hirano bodies,
β-amyloid deposition in the small cortical blood vessels, and neu­
ronal loss in the limbic area.63
Many biochemical abnormalities have been described in
patients with Alzheimer’s disease. A decrease in the neurotrans­
mitter acetylcholine is characteristic. Levels of the enzyme choline
acetyltransferase, which synthesizes acetylcholine in the brain, can
be reduced to 20% of that in age-matched control subjects.64
Several risk factors for Alzheimer’s disease are recognized,
including advancing age, family history, low education level,
hypercholesterolemia, and head trauma. The apolipoprotein E
epsilon 4 allele on chromosome 19 has been associated with both
familial and sporadic late-onset Alzheimer’s disease. Apolipopro­
tein E is responsible for transporting of the cholesterol and phos­
pholipids necessary for dendritic and synaptic repair. There are
several allelic variants, but those homozygous or heterozygous for
the E4 variant have an increased risk for the development and
expression of the disease.64 Abnormalities on chromosomes 1 and
14 also have been associated with Alzheimer’s disease.
The frontotemporal dementias are less prevalent than Alzheim­
er’s disease and are categorized by a frontal and temporal atrophy
caused by cell death.65 The most common histologic finding in the
frontotemporal dementias is the combination of prominent cell
1406 PART III ◆ Medicine and Surgery / Section Seven • Neurology
loss and gliosis in frontal and temporal regions of the cortex,
termed dementia lacking distinctive histology.66
Approximately 15 to 20% of dementias are caused by multiple
vascular insults to the CNS; the resulting deficit is termed multiinfarct dementia. The multiple infarcts typically involve the cere­
bral hemispheres and basal ganglia. Multi-infarct dementia often
has an earlier age at onset than Alzheimer’s disease and occurs
more often in adult men and patients who have risk factors for
atherosclerosis. Approximately 29% of dementias are a mixed
variety, with components of both ischemic cerebrovascular disease
and Alzheimer’s dementia.64,67
Inflammatory conditions of the CNS caused by conventional
viruses include subacute sclerosing panencephalitis from measles
virus infection, progressive multifocal leukoencephalopathy from
infection by the JC virus (a papovavirus), progressive rubella
encephalitis, and infection associated with HIV disease. The
unconventional viral infections include kuru, Creutzfeldt-Jakob
disease (CJD), and variant CJD (which appears to be linked to
bovine spongiform encephalopathy, the pathologic process in
“mad cow disease”) and are associated with minimal inflamma­
tory histopathologic changes in the CNS; these diseases cause a
fine vacuolation of the nervous tissue and hence are referred to as
subacute spongiform viral encephalopathies.68
Slow virus infections of the CNS can cause a progressive demen­
tia that is irreversible. With these infections, months to years pass
between infection with the virus and the appearance of clinical
illness. Slow virus infections of the CNS are caused by both con­
ventional viruses and unconventional viruslike agents known as
prions. A prion is a proteinaceous infectious particle with the
apparent ability to start a chain reaction that changes the shape of
benign protein molecules into abnormal, slowly destructive forms.
Prions are present in CJD and variant CJD.68
One of the most prevalent slow virus infections causing pro­
gressive dementia is HIV-1 infection. HIV may produce a primary
neurotrophic disorder in addition to causing the immunologic
compromise that permits other viruses to replicate and damage
nervous tissue.
HIV dementia or AIDS dementia complex occurs in approxi­
mately one fourth of patients with AIDS. It is believed to be caused
by the HIV-1 virus targeting the microglial cells and the macro­
phages, which may produce cytotoxic substances such as tumor
necrosis factor and interleukins. Pathologic changes occur mostly
in the hippocampus and basal ganglia and include atrophy, ven­
tricular dilation, and fibrosis.69,70
Several of the potentially reversible causes of dementia also are
associated with neuropathologic or neurochemical abnormalities.
Normal-pressure hydrocephalus generally affects younger people;
50% of patients are younger than 60 years. Most of the conditions
that cause hydrocephalus involve a defect in uptake of CSF by
arachnoid villi, which results in gradual ventricular dilation.
Chronic, heavy ethanol consumption is associated with demen­
tia. The neurotoxicity of ethanol appears to be independent of
thiamine deficiency. Heavy chronic alcohol consumption causes
cerebral cortical atrophy, but no single alcohol-related dementia
syndrome exists. It is estimated that approximately 20% of chroni­
cally demented patients have a history of alcoholism.
Clinical Features
The symptoms, signs, and progression of chronic cognitive
impairment rarely are so diagnostic as to permit identification of
the specific cause of the dementia. Alzheimer’s disease begins
insidiously. Signs and symptoms of cognitive dysfunction may
be present for months to years before the diagnosis is made.
The earliest symptoms and signs of Alzheimer’s disease often are
vague and nonspecific; patients manifest anxiety, depression,
insomnia, frustration, and somatic complaints that often are more
prominent than the memory loss. Patients often deny any
cognitive deficits and change the subject of the conversation fre­
quently rather than admit their increasing forgetfulness. Physi­
cians often overlook the subtle signs of dementia in this phase of
the disease.71
Depression often is the initial manifestation of Alzheimer’s
disease and is present in up to 40% of cases. Early in the illness,
short-term memory is affected, with forgetfulness of recent events
such as appointments and names of new acquaintances. Patients
often repeat questions. The memory impairment may cause them
to withdraw from social situations and recreational pursuits.
Attempts to perform complex tasks may produce anxiety and
confusion. The patient often has difficulty with interpersonal rela­
tionships. Affect may be shallow and labile, and minor events may
trigger inappropriate laughter or tears. Compensation for early
deficits includes excessive orderliness and avoidance of situations
in which the defects may be observed. Patients in this early phase
who are treated with antidepressants with anticholinergic proper­
ties may experience worsening of their symptoms. Sedativehypnotics prescribed for anxiety also may accelerate cognitive
dysfunction.
As the dementia progresses, cognitive deficits are more obvious
and should be readily apparent on a mental status examination.
Problems with recent memory, impairment of remote memory,
language deficits, and difficulty with spontaneous speech may be
noted. With moderate severity of the disease, patients have diffi­
culty naming objects (dysnomia). As many as 50% of patients have
delusions, usually of the paranoid type. Atypical presentations of
Alzheimer’s disease include aphasia, visual agnosia, right parietal
lobe syndrome, focal neurologic findings, extrapyramidal signs,
gait disturbances, and pure memory loss. In the final stage of
dementia, patients exhibit marked cognitive impairment, apraxia,
and significant personality changes. They often are bedridden and
unable to perform any of the routine activities of daily living.
Because Pick’s disease dementia affects the frontal and temporal
lobes, patients often have frontal lobe release signs, including dra­
matic behavioral changes of disinhibition and social inappropri­
ateness. Basal ganglia degenerative disorders that have dementia
as a prominent feature are Huntington’s chorea, Parkinson’s
disease, and Wilson’s disease. One of several features that distin­
guish cortical from subcortical dementias is a prominent move­
ment disorder, including posturing, ataxia, tremor, and chorea,
that tends to occur early in the illness. Other features of these
dementias include slowness of speech, hypotonia, and dysarthria,
which can progress to mutism.72
Patients with vascular dementia have a stepwise deterioration
in memory and cognitive function with each cerebrovascular
insult. The clinical presentation may follow one of two scenarios.
In the more common scenario, the patient suffers several strokes
that involve large volumes of cortical and subcortical structures in
both hemispheres. The patient then exhibits dementia along with
other neurologic disabilities (e.g., focal weakness, hyperreflexia,
extensor plantar response). In a second group of patients, the
presentation is more subtle. These patients characteristically
are hypertensive and suffer multiple tiny infarcts (lacunae) that
involve deep subcortical structures. There may be no focal neuro­
logic residua except progressive dementia with psychomotor retar­
dation. Aggressive antihypertensive therapy in the very elderly
does not reduce the incidence of dementia.73
The clinical manifestations of slow virus CNS infections are
protean. After an insidious onset of mental deterioration in sub­
acute sclerosing panencephalitis, a rapid progression ensues that
is associated with myoclonic jerks, incoordination, and ataxia. In
progressive multifocal leukoencephalopathy, neurologic signs and
symptoms reflect diffuse asymmetrical involvement of both cere­
bral hemispheres. Sporadic CJD, of unknown etiology, tends to
affect older people, with a rate of disease among those 50 to 70
Chapter 104 / Delirium and Dementia 1407
years of age of 1 case per million. Among these patients, rapidly
evolving dementia with myoclonus is characteristic. The hall­
marks of the disorder are mental deterioration, multisystem neu­
rologic signs, myoclonus, and typical electroencephalographic
changes that evolve during months. Variant CJD affects younger
patients (median age of 24 years), with key features that include
early affective symptoms progressing to cognitive impairment and
gait disturbances and ultimately leading to progressive neurologic
deterioration. The incubation period appears to be in the range
of 10 to 15 years, and most patients die within 14 months after
the clinical onset of symptoms.68
The most common treatable dementia is pseudodementia, or
depression. The clinical distinction between depression and
dementia is difficult, and the coexistence of depression and
dementia is common in people with mild dementia. A number of
distinguishing features suggest that the problem is depression
rather than dementia: the onset of cognitive changes in pseudode­
mentia often can be pinpointed, and symptoms usually are of
short duration before medical help is sought. The progression of
symptoms is rapid, and the family usually is aware of the severity
of the dysfunction. A history of psychiatric illness is common.
Patients with pseudodementia usually complain of cognitive dys­
function and emphasize their failures and disabilities. The affec­
tive change often is pervasive, and the patient makes little effort
to perform simple tasks. Loss of social skills usually occurs early
in the illness, and patients communicate a strong sense of distress
and inability to function. Intellectual functioning in pseudode­
mentia often is difficult to assess because of lack of patient coop­
eration or inconsistent findings on neuropsychometric testing.
Attention and concentration often are intact, but patients com­
monly give answers such as “I don’t know” on tests of orientation,
concentration, and memory. Memory losses for recent and remote
events usually are equally severe, and variability in the perfor­
mance of tasks with similar degrees of difficulty may be marked.
Tasks of high capacity (e.g., testing of delayed memory with dis­
traction) may be helpful in identifying the depressed patient.74
The classic triad of progressive dementia, ataxia, and urinary
incontinence occurs in patients with normal-pressure hydroceph­
alus, which typically affects patients who are younger than those
with primary degenerative dementia. More than half of the
reported cases are in persons younger than 60 years. Hydrocepha­
lus secondary to previous head trauma or infection carries a more
favorable prognosis than that for primary hydrocephalus.
In approximately 20% of the reversible cases, dementia is sec­
ondary to an intracranial mass. Patients may exhibit focal or non­
focal neurologic signs.75 Of the reversible dementias, 10 to 15%
are secondary to medications or chemical intoxications, frequently
compounding a history of heavy alcohol use. Geriatric patients
have increased susceptibility to the toxicities owing to polyphar­
macy and age-related changes in metabolism. The clinical presen­
tation of a patient with a drug-related or toxin-related dementia
may be indistinguishable from that of a patient with a primary
degenerative process.
Family or friends usually bring the patient to the ED because
of a sudden worsening in mental status, a change in the patient’s
activities (e.g., refusal to eat), or a change in the ability of the
caregiver to manage the patient. Presentations vary by the cause
of the dementia and the stage of progression. Many elders with
dementia have a superimposed delirium on presentation.
Differential Considerations
Subacute or chronic cognitive decline may be secondary to a
dementing illness or can be a manifestation of senescent forgetful­
ness, delirium, or depression. Senescent forgetfulness is an almost
inevitable reality of aging. Mild impairment of both short-term
and long-term memory is usual. Unlike in dementia, the cognitive
disturbance in senescent forgetfulness does not interfere with
work or customary social activity. The distinction between senes­
cent forgetfulness and mild cognitive impairment is not well
defined.
In most cases, the clinical distinction between delirium and
dementia is obvious. As stated previously, the onset of symptoms,
progression of signs and symptoms, perceptual disturbances, pos­
sible presence of abnormalities on assessment of vital signs, and
fluctuations in the level of consciousness are key distinguishing
features.
Diagnostic Strategies
The evaluation of the patient with possible dementia should
include a focused medical and psychiatric history and medication
history plus a collateral history from family and friends. Physical
examination should include a detailed neurologic examination
with mental status evaluation. Dementia often goes unrecognized
in the patient who is alert, pleasant, and cooperative. A validated
cognitive evaluation test can play a key role in the early identifica­
tion of dementia in patients who have maintained social and
conversational ability.
Alzheimer’s disease is a clinical diagnosis typically made on
probability; no routine available laboratory tests have been found
to confirm the presence of the disorder (although MRI scan, func­
tional scans looking at regional blood flow or glucose metabolism,
assay for specific biomarkers, and CSF analysis can significantly
increase the probability of the presence of the disease). The physi­
cal examination is rarely helpful in detecting treatable dementias
because of the considerable clinical overlap with irreversible
dementias. Data clearly supporting or refuting the ordering of
“routine” laboratory studies for evaluation of dementia are lacking;
however, a number of studies are recommended to exclude treat­
able causes (Box 104-4). For patients with suspected undiagnosed
dementia presenting to the ED, a baseline laboratory evaluation,
BOX 104-4 Diagnostic Evaluation for Dementia
History (patient, family, friends)
Review of medications
Physical examination, including neurologic evaluation
Mental status examination
Laboratory evaluation
Complete blood count
Electrolyte and glucose levels
Liver and renal function studies
Urinalysis
Thyroid function studies
VDRL and FTA assays
Radiographic evaluation
Chest radiograph
Head CT scan
Additional evaluation
Blood and urine screens for drugs and heavy metals
Erythrocyte sedimentation rate
HIV screen
Antinuclear antibody
Oxygen saturation, arterial blood gas analysis
Serum vitamin B12 and folate levels
Lumbar puncture
MRI head scan
Electroencephalogram
Neuropsychometric testing
Evoked potentials (visual, brainstem auditory, somatosensory)
CT, computed tomography; FTA, fluorescent treponemal antibody; HIV, human
immunodeficiency virus; MRI, magnetic resonance imaging; VDRL, Venereal
Disease Research Laboratory.
1408 PART III ◆ Medicine and Surgery / Section Seven • Neurology
including CBC, comprehensive metabolic panel, and urinalysis, is
indicated. If neurosyphilis is clinically suspected, a serum fluores­
cent treponemal antibody absorption test should be performed
in addition to a Venereal Disease Research Laboratory (VDRL)
test because the serum VDRL assay may yield negative results in
patients with tertiary syphilis. The radiologic evaluation should
include a non–contrast-enhanced head CT scan. The CT scan is
used to diagnose or to exclude the presence of hydrocephalus or
space-occupying lesions, and CT findings may support a vascular
etiology for the dementia.
Patients require additional laboratory tests on follow-up evalu­
ation; such tests may include determination of serum vitamin B12
and folate levels, thyroid function studies, estimation of erythro­
cyte sedimentation rate, fluorescent antinuclear antibody assay,
measurement of urine corticosteroid levels, and, if indicated by
history, urine screens for drugs and heavy metals. Selected patients
should undergo a lumbar puncture with CSF analysis, MRI, posi­
tron emission tomography scan, electroencephalography (in CJD,
characteristic slowing and periodic complexes may be electroen­
cephalographic features), neuropsychological testing, and testing
of visual evoked potentials, brainstem auditory evoked potentials,
and somatosensory evoked potentials. The EEG rarely is helpful
in establishing the diagnosis of senile dementia. An MRI finding
of medial temporal atrophy suggests Alzheimer’s disease but is not
specific or sensitive for diagnosis of this disorder.76
Treatment and Disposition
Reversible dementias and conditions that cause worsening of base­
line dementia require early diagnosis and treatment of the under­
lying disorder if previous cognitive function is to be restored.
Determination of reversible causes of dementia during the ED
evaluation occasionally is possible on the basis of the history
(including medication history), physical examination, and head
CT scan. Patients with acute changes in mental status or a rela­
tively rapid onset of symptoms will require hospitalization for
comprehensive evaluation. Patients presenting with recent gradual
decline in cognitive function without an underlying acute medical
condition can undergo further evaluation on an outpatient basis.
Pharmacotherapy approved by the FDA for the treatment of
mild to moderate Alzheimer’s disease includes the cholinesterase
inhibitors donepezil (Aricept), rivastigmine (Exelon), and galan­
tamine (Razadyne). There are multiple randomized, placebocontrolled, large-scale clinical trials with these drugs establishing
efficacy in improving cognitive functions, overall evaluation, and
activities of daily living in patients with mild to moderate demen­
tia. These drugs are not considered disease modifying, and there
are limited data at present on the benefit of these drugs beyond 2
or 3 years (a significant number of patients discontinue medica­
tions because of side effects). The most common side effect of
these agents is due to the cholinergic effects, including nausea,
vomiting, and diarrhea. In 2003, the FDA approved memantine
(Namenda), a disease-modifying agent that helps regulate the
excitatory effects of glutamate by antagonizing the N-methyl-daspartate receptor. Whether this drug alters the underlying disease
process is unclear, but short-term studies show improved cogni­
tion in patients with moderate and moderate to severe Alzheimer’s
disease with memantine.77,78 There are conflicting studies on the
effectiveness of other agents, such as gingko biloba, vitamin E,
nonsteroidal agents, and statins. Estrogen replacement is not indi­
cated for cognitive improvement or maintenance in women with
Alzheimer’s disease and can be detrimental. Ultimately, the key to
altering the course of the disease is halting neuron loss. In severe
dementia, the goal of management is supportive care.
Many therapies currently are under investigation for the
modulation and early treatment of Alzheimer’s disease. These
therapies include antibiotics (directed against Chlamydophila
pneumoniae), secretase modulators to reduce serum β-amyloid
levels, immunization to reduce amyloid plaque burden, chelators
to promote dissolution of β-amyloid, nonsteroidal antiinflammatory medications, supplementation with omega-3 fatty
acids, and testosterone.79,80
Increasing evidence suggests that certain nonpharmacologic
measures, including behavioral methods and avoidance of envi­
ronmental triggers, may be effective in reducing agitation and
anxiety in patients with dementia.81 On occasion, medications are
needed for behavioral symptoms of dementia. Affected patients
typically do not improve with anxiolytics. Adverse effects offset
the modest advantages in the efficacy of antipsychotic drugs for
the treatment of psychosis, aggression, or agitation in many
patients with Alzheimer’s disease, and these drugs should be
avoided when possible.82,83 However, agitation can be controlled
with a small dose of the butyrophenone haloperidol.84 The cardio­
vascular toxicity of this drug is minimal, and it is reasonably well
tolerated in elders. Clozapine also has been shown to be effective
in treating psychosis associated with both Alzheimer- and
Parkinson-type dementias.85 In April 2005, the FDA issued a black
box warning that the use of atypical antipsychotics to treat elderly
patients with dementia was associated with an increased risk for
death compared with placebo. Atypical antipsychotics are rela­
tively contraindicated in this group of patients because of the
association with an increased risk of hospitalization and death.86,87
Agitation may occasionally be due to unrecognized depression in
dementia, and a trial of selective serotonin reuptake inhibitors
may be warranted.88 Temazepam (Restoril) is the drug of choice
for sleep disturbance. The half-life of temazepam is 8 to 10 hours
for patients of all ages, and the drug bypasses the oxidative hepatic
enzyme system.
On occasion, patients are brought to the ED because of a crisis
due to family stress from continuous care of the person with
dementia. A brief nursing home stay or other institutional stay
(respite program) may give the family time to mobilize resources
to resume the home care regimen. Social workers can play a vital
role in attempting to facilitate management of these patients.
KEY CONCEPTS
■ Delirium is an acute condition characterized by an altered
level of consciousness, disorganized thinking, and inattention.
It develops during a short time, and symptoms tend to
fluctuate during hours to days. A thorough investigation of
possible causes of the delirium should be undertaken in the
ED.
■ Dementia is a chronic condition characterized by memory loss
and cognitive impairment. It is slow in onset and progressive
in nature. This disorder has many causes, several of which
are reversible with treatment. It is essential to resist the
temptation to classify dementia as a “futile” disease, and a
search for underlying medical conditions that may be
worsening a dementing illness is indicated.
■ Patients with either dementia or psychiatric disorders may
present with superimposed delirium, often making
identification of the underlying cause of their abnormal
behavior difficult. When the diagnosis is in doubt, possible
causes of delirium should be specifically excluded.
■ The clinician should be wary of attributing behavioral
disturbances to psychiatric illness in the presence of abnormal
vital signs or abnormal sensorium.
The references for this chapter can be found online by
accessing the accompanying Expert Consult website.
Chapter 104 / Delirium and Dementia 1408.e1
References
1. American Psychiatric Association: Diagnostic and Statistical Manual of
Mental Disorders, 4th ed. text rev. Washington, DC: American Psychiatric
Association; 2000.
2. Inouye SK, Ferrucci L: Elucidating the pathophysiology of delirium and
the interrelationship of delirium and dementia. J Gerontol A Biol Sci
Med Sci 2006; 61:1277-1280.
3. Fick DM, Agostini JV, Inouye SK: Delirium superimposed on dementia:
A systemic review. J Am Geriatr Soc 2002; 50:1723-1732.
4. Meagher DJ, Trzepacz PT: Motoric subtypes of delirium. Semin Clin
Neuropsychiatry 2000; 5:75-85.
5. Hustey FM, Meldon SW: The prevalence and documentation of
impaired mental status in elderly emergency department patients. Ann
Emerg Med 2002; 39:248.
6. Elie MJ: Delirium risk factors in elderly hospitalized patients. J Gen
Intern Med 1998; 13:204.
7. Flacker JM, et al: The association of serum anticholinergic activity with
delirium in elderly medical patients. Am J Geriatr Psychiatry 1998;
6:31-41.
8. Rivera W, et al: Central nervous system toxicity manifestations of drug
toxicity. Emerg Med Rep 2003; 24:12.
9. Inouye SK: Delirium in older persons. N Engl J Med 2006; 354:1157.
10. Talbot-Stern JK, et al: Psychiatric manifestations of systemic illness.
Emerg Med Clin North Am 2000; 18:199.
11. Hohl CM, et al: Polypharmacy, adverse drug-related events, and
potential adverse drug interactions in elderly patients presenting to an
emergency department. Ann Emerg Med 2001; 38:661.
12. Folstein MF, Folstein SE, McHugh PR: “Mini-mental state”: A practical
method for grading the cognitive state of patients for the clinician. J
Psychiatr Res 1975; 12:189.
13. Cullen B, O’Neill B, Evans JJ, Coen RF, Lawlor BA: A review of screening
tests for cognitive impairment. J Neurol Neurosurg Psychiatry 2007;
78:790-799.
14. American Psychiatric Association Practice Guidelines: Practice guidelines
for the treatment of patients with delirium. Am J Psychiatry 1999;
156(Suppl):5.
15. Wilber ST, et al: An evaluation of two screening tools for cognitive
impairment in older emergency department patients. Acad Emerg Med
2005; 12:612.
16. Petersen RC: Practice parameter: Early detection of dementia: Mild
cognitive impairment (an evidenced-based review). Neurology 2001;
56:1133.
17. Duff Canning SJ, et al: Diagnostic utility of abbreviated fluency
measures in Alzheimer disease and vascular dementia. Neurology 2004;
62:556.
18. Huff JS, et al: The quick confusion scale in the ED: Comparison with the
Mini-Mental State Examination. Am J Emerg Med 2001; 19:461.
19. Inouye SK, et al: Clarifying confusion: The confusion assessment
method: A new method for detection of delirium. Ann Intern Med 1990;
113:941.
20. Zou Y, et al: Detection and diagnosis of delirium in the elderly:
Psychiatrist diagnosis, confusion assessment method or consensus
diagnosis? Int Psychogeriatr 1998; 10:303.
21. Witlox J, et al: Delirium in elderly patients and the risk of post-discharge
mortality, institutionalization, and dementia: A meta analysis. JAMA
2010; 304:443-451.
22. Schmidt P, et al: The effects of positional restraint on heart rate and
oxygen saturation. J Emerg Med 1999; 17:777.
23. Stratton SJ, et al: Factors associated with sudden death of individuals
requiring restraint for excited delirium. Am J Emerg Med 2001; 19:187.
24. Lonergan E, Britton AM, Luxenberg J, Wyller T: Antipsychotics for
delirium. Cochrane Database Syst Rev 2007; 2:CD005594.
25. Seeman P: Atypical antipsychotics: Mechanism of action. Can J
Psychiatry 2002; 47:27.
26. Daniel DG, et al: Intramuscular (IM) ziprasidone 20 mg is effective in
reducing acute agitation associated with psychosis: A double-blind,
randomized trial. Psychopharmacology (Berl) 2001; 155:128.
27. Brook S, et al: Intramuscular (IM) ziprasidone compared with
intramuscular haloperidol in the treatment of acute psychosis. J Clin
Psychiatry 2000; 61:933.
28. Battaglia J, et al: Calming versus sedative effects of intramuscular
olanzapine in agitated patients. Am J Emerg Med 2003; 21:192.
29. Wright P, et al: Double blind, placebo-controlled comparison of
intramuscular olanzapine and intramuscular haloperidol in the
treatment of acute agitation. Am J Psychiatry 2001; 158:1149.
30. Kales HC, et al: Trends in antipsychotic use in dementia 1999-2007.
Arch Gen Psychiatry 2011; 68:190-197.
31. Bailey P, Norton R, Karan S: The FDA droperidol warning: Is it justified?
Anesthesiology 2002; 97:288.
32. Thomas H, Schwartz E, Petrilli R: Droperidol versus haloperidol for
chemical restraint of agitated and combative patients. Ann Emerg Med
1992; 21:407.
33. Lonergan E, Luxenberg J, Areosa SA, Wyller TB: Benzodiazepines for
delirium. Cochrane Database Syst Rev 2009; 1:CD006379. DOI:
10.1002/14651858. CD006379.pub2.
34. Pandharipande P, et al: Lorazepam is an independent risk factor for
transitioning to delirium in intensive care unit patients. Anesthesiology
2006; 104:21.
35. Jacobi J, et al: Clinical practice guidelines for the use of sedatives and
analgesics in the critically ill adult. Crit Care Med 2002; 30:119.
36. Schillevoort I: Risk of extrapyramidal syndromes with haloperidol,
risperidone, and olanzapine. Ann Pharmacother 2001; 35:1517.
37. Sharma ND, et al: Torsades de pointes associated with intravenous
haloperidol in critically ill patients. Am J Cardiol 1998; 81:238.
38. Bergmann MA, Murphy KM, Kiely DK, Jones RN, Marcantonio ER: A
model for management of delirious postacute care patients. J Am Geriatr
Soc 2005; 53:1817.
39. Battaglia J, et al: Haloperidol, lorazepam, or both for psychotic agitation:
A multicenter, prospective, double-blind emergency department study.
Am J Emerg Med 1997; 15:335.
40. Cook IA: Guideline Watch: Practice Guideline for the Treatment of
Patients with Delirium. Washington, DC: American Psychiatric
Association; 2004.
41. Skrobik YK, et al: Olanzapine vs haloperidol: Treating delirium in a
critical care setting. Intensive Care Med 2004; 30:444.
42. Sipahimalani A, Massand PS: Use of risperidone in delirium: Case
reports. Ann Clin Psychiatry 1997; 9:105.
43. Ravona-Springer R, et al: Delirium in elderly patients treated with
risperidone: A report of three cases. J Clin Psychopharmacol 1998;
18:171.
44. Sipahimalani A, Masand PS: Olanzapine in the treatment of delirium.
Psychosomatics 1998; 39:422.
45. Naess AC: Patient autonomy in emergency medicine. Med Health Care
Philos 2001; 4:71.
46. Inouye SK, et al: Risk factors for delirium at discharge: Development
and validation of a predictive model. Arch Intern Med 2007; 167:1406.
47. McCusker J, et al: Delirium predicts 12-month mortality. Arch Intern
Med 2002; 162:457.
48. Cole MG, et al: Systematic detection and multidisciplinary care of
delirium in older medical inpatients: A randomized trial. CMAJ 2002;
167:753.
49. Knopman DS, et al: Incidence and causes of nondegenerative
nonvascular dementia: A population-based study. Arch Neurol 2006;
63:218.
50. Hejl A, Hogh P, Waldemar G: Potentially reversible conditions in 1000
consecutive memory clinic patients. J Neurol Neurosurg Psychiatry 2002;
73:390.
51. Alzheimer A: Uber eine eigenartige Erkrankung der Hirnrinde. Allerg Z
Psychiatr 1907; 64:146.
52. Ferri CP, et al: Global prevalence of dementia: A Delphi consensus study.
Lancet 2005; 366:2112.
53. National Institutes of Health, National Institute on Aging: Progress
Report on Alzheimer’s Disease 1999. Bethesda, Md: U.S. Department of
Health and Human Services; 1999. NIH Publication No. 99-4664.
54. Kukull WA: Dementia epidemiology. Med Clin North Am 2002; 86:573.
55. Morris JC, et al: Mild cognitive impairment represents early-stage
Alzheimer disease. Arch Neurol 2001; 58:397-405.
56. Tschanz JT, et al: Dementia: The leading predictor of death in a defined
elderly population: The Cache County Study. Neurology 2004; 62:1156.
57. Roberts GW, Allsop D, Bruton C: The occult aftermath of boxing. J
Neurol Neurosurg Psychiatry 1990; 53:373.
58. Mckee AC, et al: Chronic traumatic encephalopathy in athletes:
Progressive tauopathy after repetitive head injury. J Neuropathol Exp
Neurol 2009; 68:709-735.
59. Belman AL: HIV-1 infection and AIDS. Neurol Clin 2002; 20:983.
60. Winblad B: Major depression in a population of demented and
nondemented older people: Prevalence and correlates. J Am Geriatr Soc
2002; 46:27.
61. Feldman H, et al: Behavioral symptoms in mild cognitive impairment.
Neurology 2004; 62:1199-1201.
62. Tanzi, RE: Tangles and neurodegenerative disease—a surprising twist.
N Engl J Med 2005; 353:1835.
63. Gandy S: The role of cerebral amyloid beta accumulation in common
forms of Alzheimer disease. J Clin Invest 2005; 115:1121.
64. Cummings JL: Alzheimer’s disease. N Engl J Med 2004; 351:56.
1408.e2 PART III ◆ Medicine and Surgery / Section Seven • Neurology
65. Knopman DS: An overview of common non-Alzheimer dementias. Clin
Geriatr Med 2001; 17:281.
66. Giannakopoulos P, Hof PR, Bouras C: Dementia lacking distinctive
histopathology: Clinicopathological evaluation of 32 cases. Acta
Neuropathol (Berl) 1995; 89:346.
67. Chui HC, et al: Clinical criteria for the diagnosis of vascular dementia: A
multicenter study of comparability and interrater reliability. Arch Neurol
2000; 57:191.
68. Tyler KL: Creutzfeldt-Jakob disease. N Engl J Med 2003; 384:681.
69. Bensalem MK, Berger JR: HIV and the central nervous system. Compr
Ther 2002; 28:23.
70. Sotrel A, Dal Canto MC: HIV-1 and its causal relationship to
immunosuppression and nervous system disease in AIDS: A review.
Hum Pathol 2000; 31:1274.
71. Finkel SI: Behavioral and psychological symptoms of dementia. Clin
Geriatr Med 2003; 19:799.
72. Graham NL, Bak T, Patterson K, Hodges JR: Language function and
dysfunction in corticobasal degeneration. Neurology 2003; 61:493.
73. Peters R, et al: Incident dementia and blood pressure lowering in the
Hypertension in the Very Elderly Trial cognitive function assessment
(HYVET-COG): A double-blind placebo controlled trial. Lancet Neurol
2008; 7:683-689.
74. Peters KR, et al: Characterizing neuropsychiatric symptoms in subjects
referred to dementia clinics. Neurology 2006; 66:523.
75. Clarfield AM: The decreasing prevalence of reversible dementia: An
updated meta-analysis. Arch Intern Med 2003; 163:2219.
76. Barnes J, et al: Measurement of the amygdala and hippocampus in
pathologically confirmed Alzheimer disease and frontal lobe
degeneration. Arch Neurol 2006; 63:1434.
77. Reisberg B, et al: A 24-week open-label extension study of memantine in
moderate to severe Alzheimer disease. Arch Neurol 2006; 63:49.
78. McShane R, Areosa Sastre A, Minakaran N: Memantine for dementia.
Cochrane Database Syst Rev 2006; 2:CD003154.
79. Sano M, et al: A controlled trial of selegiline, alpha-tocopherol, or both
as treatment for Alzheimer’s disease. The Alzheimer’s Disease
Cooperative Study. N Engl J Med 1997; 336:1216.
80. Siemers ER, et al: Effects of a gamma-secretase inhibitor in a
randomized study of patients with Alzheimer’s disease. Neurology 2006;
66:602.
81. Ayalon L, et al: Effectiveness of nonpharmacological interventions for
the management of neuropsychiatric symptoms in patients with
dementia: A systemic review. Arch Intern Med 2006; 166:2182.
82. Rochon PA, et al: Antipsychotic therapy and short-term serious events in
older adults with dementia. Arch Intern Med 2008; 168:1090.
83. Kuehn BM: FDA warns antipsychotic drugs may be risky for elderly.
JAMA 2005; 293:2462.
84. Tariot PN, et al: Pharmacologic therapy for behavioral symptoms of
Alzheimer’s disease. Clin Geriatr Med 2001; 17:359.
85. Low-dose clozapine for the treatment of drug-induced psychosis in
Parkinson’s disease. The Parkinson Study Group. N Engl J Med 1999;
340:757.
86. Schneider LS, et al: Effectiveness of atypical antipsychotic drugs in
patients with Alzheimer’s disease. N Engl J Med 2006; 355:1525.
87. Schneider LS, et al: Risk of death with atypical antipsychotic drug
treatment for dementia: Meta-analysis of randomized placebo-controlled
trials. JAMA 2005; 294:1934.
88. Fickle SI, et al: A randomized placebo-controlled study of the efficacy
and safety of sertraline in the treatment of the behavioral manifestations
of Alzheimer’s disease in outpatients treated with donepezil. Int J Geriatr
Psychiatry 2004; 19:9.